TY - JOUR
T1 - Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice
AU - Beetler, Danielle J.
AU - Bruno, Katelyn A.
AU - Watkins, Molly M.
AU - Xu, Vivian
AU - Chekuri, Isha
AU - Giresi, Presley
AU - Di Florio, Damian N.
AU - Whelan, Emily R.
AU - Edenfield, Brandy H.
AU - Walker, Sierra A.
AU - Morales-Lara, Andrea C.
AU - Hill, Anneliese R.
AU - Jain, Angita
AU - Auda, Matthew E.
AU - Macomb, Logan P.
AU - Shapiro, Kathryn A.
AU - Keegan, Kevin C.
AU - Wolfram, Joy
AU - Behfar, Atta
AU - Stalboerger, Paul G.
AU - Terzic, Andre
AU - Farres, Houssam
AU - Cooper, Leslie T.
AU - Fairweather, De Lisa
N1 - Funding Information:
The authors thank the Dennis Dickson Histology Group for their work embedding and staining slides for this project. This group includes Dennis W. Dickson, Linda Rousseau, Virginia Phillips, Ariston Libraro, and Monica Castanedes. The authors also thank the Mayo Microscopy and Cell Analysis Core for experimental and technical support. This work was partially supported by the Mayo Clinic Center for Regenerative Medicine in Florida (D.F. and J.W.), the Mayo Clinic Center for Biomedical Discovery (J.W.), National Institutes of Health (NIH) TL1 TR002380 (D.J.B., D.N.D., E.R.W., and D.F.), National Institute of Allergy and Infectious Diseases under award numbers R21 AI152318 (D.F. and J.W.), R21 AI145356 (D.F.), R21 AI154927 (D.F.), R21 AI163302 (K.A.B.), National Heart Lung and Blood Institute under award number R01 HL164520 (D.F.), the American Heart Association under award number 20TPA35490415 (D.F. and J.W.), the American Heart Association under award number 23SCEFIA1153413 (K.A.B.), and The University of Queensland (J.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Publisher Copyright:
© 2023 The Authors. Small published by Wiley-VCH GmbH.
PY - 2023
Y1 - 2023
N2 - Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.
AB - Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1β), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.
KW - TLR4
KW - cardiomyopathy
KW - complement
KW - microRNA
KW - regenerative medicine
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U2 - 10.1002/smll.202303317
DO - 10.1002/smll.202303317
M3 - Article
AN - SCOPUS:85168623342
JO - Small
JF - Small
SN - 1613-6810
ER -